The Carver College of Medicine at The University of Iowa, Iowa City, IA Ophthalmology and Visual Science, Electrical and Computer Engineering, The Howard Hughes Medical Institute, Iowa City, IA

A.P. Chiang

Ophthalmology and Visual Science, Electrical and Computer Engineering, The University of Iowa, Iowa City, IA

T. Scheetz

The Carver College of Medicine at The University of Iowa, Iowa City, IA Ophthalmology and Visual Science, Electrical and Computer Engineering, Pediatrics, Biomedical Engineering, The University of Iowa, Iowa City, IA

K.A. Kim

Biostatistics, The University of Iowa, Iowa City, IA

R.E. Swiderski

The Carver College of Medicine at The University of Iowa, Iowa City, IA Pediatrics, Biomedical Engineering,

D.Y. Nishimura

The Carver College of Medicine at The University of Iowa, Iowa City, IA Pediatrics, Biomedical Engineering,

L.M. Affatigato

The Carver College of Medicine at The University of Iowa, Iowa City, IA Ophthalmology and Visual Science, Electrical and Computer Engineering,

Purpose: :
To investigate the hypothesis that functionally relatedgenes will exhibit coordinated variation of expression in responseto the genetic permutation associated with a cross of distantly–related,highly–inbred rat strains.

Methods: :
Two inbred strains of laboratory rats (SR/JR/HSD andSHR/SP) were crossed and the resultant F1 animals were inter–crossed.At 12 weeks of age, 120 healthy males of the resulting F2 generationwere euthanized. RNA was extracted from the eyes and genomicDNA was extracted from the liver of each animal. The oculargene expression of each animal was determined using AffymetrixGeneChip Rat Genome 230 2.0 Arrays, which contain 31099 probes.Pairwise correlation of gene expression was investigated bothas a marker of biological pathway membership and as a meansof identifying new disease genes.

Results: :
Eight genes previously known to cause BBS showed muchhigher correlation of expression than randomly selected expressedgenes among the 120 F2 animals. When a number of candidate genesfor BBS were evaluated for correlated expression with the eightknown BBS genes, two new genes (B1 and TRIM32) exhibited greatercorrelation than the others. Screening of the coding sequencesof these genes in BBS patients revealed disease–causingmutations.

Conclusions: :
As organisms evolve, there is an evolutionaryadvantage in linking the expression of functionally relatedgenes to the biological situations for which their functionsare needed. The evolutionary conservation of these correlatedcontrol mechanisms provides a means of detecting functionalrelationships among groups of genes. Thus, the analysis of geneexpression in the progeny of a large genetic cross can be usedto find new genes responsible for genetically heterogeneousdiseases like BBS.